Thursday, 9 June 2011

MALARIA: Professor Nick White and artesunate

9 Jun, 2011 : Anjana Ahuja

To mark the 75th anniversary of the death of Henry Wellcome and the founding of the Wellcome Trust, we are publishing a series of 14 features on people who have been significant in the Trust’s history. In our seventh piece, freelance science writer Anjana Ahuja looks at Nick White, Director of the Wellcome Trust’s South-east Asia Major Overseas Programme.Nick White
Professor Nick White wants to get up close and personal with his nemesis. Unlike many of his colleagues and co-workers, he has never contracted malaria, the disease to which he has devoted the bulk of his 30-year career, backed principally by the Wellcome Trust and the University of Oxford. And so he is now considering drastic action. “I’m actually thinking of giving it to myself,” he reveals. “Lots of scientists experiment on their own bodies. Why shouldn’t I?”
Because, I suggest tentatively, malaria is a horrible disease that causes enormous suffering and almost one million deaths a year worldwide, including a fifth of all childhood deaths in Africa? “Ah, but I can cure myself with drugs.” And with that simple riposte, White unwittingly captures much about the state of the global war against malaria today.
On the one hand, the disease is treatable with current medicines; the World Health Organization recommends a frontline treatment called artemisinin-based combination therapy (ACT). White, 60, who runs the Trust’s South-east Asia Major Overseas Programme from his base at Mahidol University in Bangkok, is largely responsible for this fresh weapon in medicine’s armoury: in 1979, he and his colleagues chanced upon a paper in a Chinese scientific journal detailing the antimalarial properties of a herb called qinghao, derived from the sweet wormwood tree. By tracking down the Chinese scientists who did the work, and then conducting their own detailed, large-scale studies on infected patients, his team were able to prove definitively that derivatives of qinghao (called qinghaosu, or, more commonly artemisinin) worked better than quinine to vanquish malaria.
Now, a potent form of artemisinin is recommended in combination with a conventional antimalarial, such as mefloquine, as the best line of defence against the disease. These therapeutic double-acts are arguably the closest that modern medicine has come to an antimalarial wonder drug: the artemisinin derivative delivers a swift, powerful punch capable of killing most of the Plasmodium falciparum parasites, while its slower-acting partner wipes out the parasitic stragglers that survive the first blow (and that, if left untreated, could become a petri dish for resistant strains to emerge).
On the other hand, malaria remains undefeated in low-income countries, particularly in Africa. How can this be? Unfortunately, eradicating the mosquito-borne scourge requires more than just a brilliant new antimalarial. It also requires global coordination, massive political and civic will, widespread health education and funding, and a vocal patient lobby. All seem a long way off: the WHO is global but has limited powers and relatively shallow coffers; the field is highly fragmented, with charities, NGOs and individual governments working alongside international programmes such as Roll Back Malaria (RMB) and the Medicines for Malaria Venture (MMV); the countries most afflicted by malaria are among the poorest, with weak health infrastructure; and, as White starkly puts it, “a mother who has walked for miles with her dying child doesn’t generally go banging on the doors of Parliament. There’s a dissociation from reality that’s easier if you’re sitting in Geneva or London, because malaria doesn’t affect you or your family. Malaria affects the disenfranchised; these are people with no votes. People like us are supposed to be acting on their behalf, but I don’t think we always do.”
He cites as an example the struggle to persuade the WHO to change its malaria-treatment guidelines in favour of ACT, despite the overwhelming evidence: “The world was very, very slow to endorse ACT. It was a protracted and painful process, and it took an incendiary paper in the ‘Lancet’ by Attaran et al. [Amir Attaran, a Canadian professor of law and medicine, is a long-term critic of global agencies charged with controlling malaria] to make the WHO change its mind.” Eventually, the WHO acknowledged that ACT was indeed the best treatment for falciparum malaria and issued definitive guidelines five years ago.
In a landmark paper published in 2005, White’s team showed that the artemisinin derivative artesunate (given by injection) reduced the mortality of severe malaria by more than one-third. This dramatic result changed the treatment guidelines for adults, but not for African children, who bear the brunt of deaths from malaria.
The battle then continued to get the guidelines changed for children (the trials that proved artemisinin’s effectiveness were carried out on adults) – a grim irony, given that children, babies and pregnant women suffer most. In November 2010, however, White’s team laid any doubts to rest with a paper in the Lancet showing that the Chinese drug also substantially cuts mortality in children. The AQUAMAT (African Quinine versus Artesunate Malaria Trial) study enrolled more than 5000 sick children across Africa: 2712 were put on the artemisinin derivative artesunate and 2713 on quinine. In the artesunate group, 230 died, compared with 297 in the quinine group. The 22 per cent difference in child mortality between the quinine and artesunate groups isn’t quite as dramatic as the 35 per cent difference seen in the adult group – but children are more likely than adults to present with fever that is not malaria. Importantly, the child study also showed that those in the artesunate group were less likely to develop severe coma, convulsions and life-threatening hypoglycaemia. On top of these clear medical advantages, the drug is easier to administer and was better tolerated, an important consideration in busy tropical hospitals.
The paper concluded that “these data…strongly suggest that parenteral artesunate should replace quinine as the treatment of choice for severe falciparum malaria worldwide”. According to one widely quoted statistic, a child dies from malaria every 45 seconds; no wonder, then, that White, who sees such suffering at first hand, told one British newspaper that it was “absolutely nuts” for doctors to keep dishing out quinine for severe malaria. He believes that doctors are suspicious of the fact that artesunate is manufactured in China, rather than by a highly regulated pharmaceutical giant in Europe or North America.
It illustrates one of the greatest challenges in the lives of researchers such as White: trying to ensure that scientific developments are picked up by policy makers and politicians to effect real change on the ground. “I count myself as a rather poor politician, and don’t consider myself good at making the case for something. The best thing I can do is to provide the evidence – to talk about it and publish it so that better politicians can do the right thing.”
He may not rate his powers of political persuasion particularly highly, but his scientific prowess is beyond doubt. The Oxford-educated doctor arrived at the Faculty of Tropical Medicine, Mahidol University in Bangkok in 1979, to work in the brand new Wellcome Trust Research Unit focusing on cerebral malaria (coma brought on by malaria). The Unit began life as, and remains, a joint initiative between the Trust, Mahidol University and the University of Oxford. He took over as head in 1986, and under his tenure, the Unit rose to become one of the most influential centres of disease research in the world, with its researchers among the most cited in tropical medicine, particularly malaria. In 2001 he handed over direction of the Thailand programme to his colleague, Professor Nick Day. He now chairs the Trust’s South-east Asia Programme. With sister collaborations in Vietnam and Laos, his research team not only made great strides in treating and controlling malaria, but also in tackling other infectious diseases. Under the leadership of Professor Jeremy Farrar, for example, the Vietnam unit has conducted pioneering investigations into H5N1, the potentially pandemic-inducing strain of the influenza virus.
It is a deep passion for science that drives White: when asked to name the high point of his career, he singles out the announcement, at the 2010 meeting of the American Society of Tropical Medicine, of the AQUAMAT trial showing artesunate’s effectiveness in children. Publication in the ‘Lancet’ was timed to follow two days later. “That paper we presented showed conclusively and irrefutably that we could save hundreds of thousands of lives a year. It doesn’t get much better than that.” And this from an academic whose career is studded with accolades, including an OBE, the Royal Society Prize in 2005 (the first time it was awarded in tropical medicine), Fellowship of the Royal Society in 2006, and, in 2010, the US$50 000 Prince Mahidol Award for Medicine in addition to the Gairdner Prize for Global Health, which comes with a purse of CAN$100 000. I mention that Sir Paul Nurse, the Nobel Prize-winning biologist who now heads the Royal Society, famously bought a motorbike with some of his prize money. But White sounds genuinely shocked at the idea of using any of the money to spoil himself, as he is entitled to do: “I love what I do. I don’t need to treat myself.” Instead, he is spending the windfall on a tuberculosis laboratory on the border between Thailand and Myanmar.

Artemisia annua (sweet wormwood)
Artemisia annua (sweet wormwood), from which artemisinin is derived.

One senses that Professor White could never revel in his achievements when there is still so far to go on the malaria front. On a scale of 0 to 10, with 0 representing malaria endemic all over the world, and 10 representing its complete global eradication, he puts us at about 7. While the disease has retreated from temperate shores, it is not yet yielding in sub-Saharan Africa and parts of Asia. Again, politics as well as science must take some of the blame: the end of colonialism and, later on, the Cold War shifted the world’s attention away from malaria eradication, a shift exacerbated by the gradual development of resistance to older antimalarials such as chloroquine. The WHO, which in 1955 had declared malaria eradication a goal, soon watered down its ambition to malaria control. It would take until the 1990s for the disease to creep back on to international agendas, piggybacking on emerging worries about tuberculosis and HIV. If ever there was a perfect time for a new antimalarial to be discovered – or rediscovered, as White prefers to say, in a gracious nod to the Chinese herbalists and scholars who studied qinghao before him – this was it.
And now, he believes, the world has a window in which to finish the job that the WHO started more than half a century ago. Although artemisinin resistance has been documented in western Cambodia, along the Thai border – possibly due to counterfeit drugs, a high turnover of migrant workers, which can spread the disease, and/or extravagant genetic diversity among parasites, which enhances the chances of a resistant strain emerging – he thinks a truly radical last push could consign the dangerous new resistant malaria to the annals of history. Given that ACT still works well in over 95 per cent of malaria cases, he has advocated targeted “mass drug administration”, in which everybody within a contained area receives antimalarials. It would require backing not just from doctors and health workers but politicians and the military – and it would be a massive feat of coordination, especially since this cradle of artemisinin resistance happens to be located in a disputed border area between Thailand and Cambodia (a planned study into the effectiveness of synthetic artemisinin was shelved recently when Cambodian ministers discovered that Thai researchers would be participating).
But despite its aggressiveness, and leaving aside the WHO’s lack of enthusiasm for such a scenario (because it involves giving antimalarials to the healthy, which could prompt drug resistance), mass drug administration is an attainable vision in specific areas. More so, he says, than the hunt for a malaria vaccine, which would be wonderful if it ever happens but still seems a long way off. He notes that, while millions of dollars from such organisations as the Bill and Melinda Gates Foundation is being poured into vaccine research, there remain cheaper, more prosaic approaches to controlling and possibly eradicating malaria. These include optimising dosages and rubber-stamping the importance of combination therapies rather than monotherapies (single medicines) so that the parasitic infection is fully annihilated, leaving no wiggle room for resistance to evolve. White says: “We have some pretty good tools but we’re not using them properly. If I told you that we often give patients the wrong doses you’d say it was ridiculous, but it’s true. It sounds boring and low-tech but I believe in a pragmatic approach. Malaria is not a static target and we have to make gains now, otherwise governments are not going to carry on putting their hands in their pockets.” He would fully endorse a “malaria tsar” who could orchestrate a master plan; such a figure does not exist, although the WHO recently appointed a new head of its Global Malaria Programme. White wouldn’t want the job himself because of – again – the politics, but he stands ready to offer technical assistance.
That eradication is being talked about once more is a tribute to the work of White and his team. It also, he says, testifies to the intellectual approach adopted by the Wellcome Trust, which has provided not only core funding for his unit since its inception but also provided the funding for the artemisinin trials in both adults and children at a time when these drugs were distinctly unfashionable. Over the past decade, the Trust has dedicated £150 million to malaria research, much of which goes to the South-east Asia Programme and two other major malaria research centres based in Kenya and Malawi.
“The Wellcome Trust are the best people to be funded by. All the time we were doing it [the artemisinin research] the Trust backed us to do difficult work in difficult places, and it really deserves credit for that,” he says. “Without its support, that work might not have been done. We live in an increasingly risk-averse culture, and today scientists write endless grant applications and have to supply justifications for their research. It’s almost as if people want you to tell them what you’ll discover before you’ve discovered it. We need organisations that have the courage to back people, and the Trust had the courage of its convictions to back us. They’re very tough when they’re assessing you but after that you get intellectual freedom, and that’s exactly what you need to get innovation.”
And, finally, what would his wife make of his plan to deliberately infect himself? Confesses White: “She’d kill me if malaria didn’t.”
Find out more about activities marking the Wellcome Trust’s 75th anniversary, including links to other features as they are published.

Anjana Ahuja is a former science columnist and feature writer for the ‘Times’. She now freelances for national newspapers and magazines, and is a co-author of ‘Selected: Why we lead, why we follow and why it matters’ (Profile Books).
Credits: Wellcome Images, Sue Snell/Wellcome Images

Malaria and Plasmodium
Wherever the Anopheles mosquito goes, malaria is never far behind. This type of mosquito – of which there are around 20 species – is a vehicle for a malaria-causing parasite called Plasmodium that targets humans. The disease is transmitted when a female mosquito bites a person who already has the parasite in their blood, and then bites another person, passing the parasite on. Anopheles thrives in hot, humid climates: it is common in Africa, Asia, parts of the Middle East, Latin America and the South Pacific. In 2008, the WHO recorded that malaria was present in 108 countries and territories worldwide.
There are 120 species of the Plasmodium genus, of which four affect humans. Of this quartet, the most serious is P. falciparum; the others are P. vivax, P. ovale and P. malariae. There have also been rare instances of people becoming infected with a monkey malaria parasite called P. knowlesi. Eighty-five per cent of malaria’s global death toll occurs in Africa not only because it is a poor continent, but also because the African mosquito species is long-lived (giving parasites a greater chance of reaching maturity before being passed on to the next victim) and has a strong bite.
The first symptoms of P. falciparum malaria, which generally appear within a few weeks of the infective bite, are similar to the onset of a minor viral illness: headache, fatigue, muscle and joint ache, and diarrhoea. As the parasite multiplies, it causes fever and vomiting. Many cases are diagnosed (or misdiagnosed) on the basis of fever.
If left untreated, the disease escalates from uncomplicated to severe malaria, which is marked by the failure of vital organs. This can lead to coma, a life-threatening plunge in blood sugar levels (hypoglycaemia) and/or kidney failure. Without treatment, the majority of people with severe malaria will die. With treatment, however, more than four out of five will recover.
There is evidence that people who are continually exposed to the parasite gain partial immunity to it. This explains why certain groups remain particularly vulnerable: babies and children whose immune systems are not fully developed are at risk, as are expectant mothers, whose immune systems change during pregnancy. Immunity in one geographical area does not guarantee immunity in another, so migration is another factor affecting malaria rates (and probably explains why drug resistance often emerges in border areas). Around 1500 travellers return to Britain with malaria each year, of whom around a dozen will die.

Treating malaria
A steady succession of medicines have emerged to combat malaria, with each gradually losing its effectiveness as the parasite evolves. Quinine emerged in the 17th century as the first known antimalarial (although historians point out that the Quechua Indians of Peru discovered its anti-fever properties long before). Its potency began fading in the 1940s, and chloroquine became the weapon of choice. This was in turn replaced by sulfadoxine-pyrimethamine (SP), which lasted another couple of decades until it was superseded by mefloquine. Resistance to this last drug appeared in the 1980s, just as excitement was beginning to build about artemisinin. The hype was justified: artemisinin is the fastest-acting antimalarial in human history, effectively curing within a couple of days.
Today, largely on the back of Professor Nick White’s research, the WHO strongly recommends artemisinin-based combination therapy as the preferred treatment option in confirmed cases of both uncomplicated and severe malaria. The treatment comprises one artemisinin derivative – such as artesunate, artemether or dihydroartemisinin – with one slower-acting partner, such as SP or mefloquine. The exact permutation given depends on which drugs work in a particular area, as drug resistance tends to be localised (which is why older drugs continue to be used in certain areas). The two different medicines are partnered up to protect against drug resistance: while the artemisinin derivative delivers a swift kill, it does not always do its duty cleanly. The older, slower drugs trail behind, finishing off the remaining parasites. To further guard against the parasite becoming resistant to ACT, the WHO recommends that, where possible, only confirmed malaria patients are treated, and that they are followed up a month later to check that no parasites have survived the medicines.
Scientists have cautioned that, as yet, there is no back-up plan if ACT eventually fails. The message is being taken seriously: Cambodia, for example, has cracked down on the supply of monotherapies (single medicines). There is a plan underway to slash the price of ACTs so steeply that they would become cheaper than counterfeit drugs. Also, synthetic artemisinin, which is under development, appears to have a different mode of parasite-killing action, offering another avenue of hope if natural ACTs go the same way as the antimalarials before them. Particularly worrisome, though, is the fact that, when it comes to artemisinin resistance, scientists have not yet figured out exactly how the parasite is fighting back against malaria’s newest wonder drug.

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